There is a great interest in therapeutic and prophylactic cancer vaccines. A variety of methods have been examined. For example, vaccines derived from whole cells have been examined and found to have a larger number of antigens, and reported to have met with some success. Tissue vaccines are derived from tumor material harvested directly from tumor-bearing individuals, and contain not only antigens associated with neoplastic cells, but also a menu of antigens associated with the tumor connective tissue and extracellular matrix.
A material known by the acronym SIS, comprised of an extracellular matrix material derived from porcine small intestinal submucosa, has been described as a material useful as a tissue scaffold. (Cook Biotech Inc., West Lafayette, Ind.).
By way of further background, a variety of extracellular matrix materials have been proposed for use in medical grafting, cell culture, and other related applications. For instance, medical grafts and cell culture materials containing submucosa derived from small intestine, stomach or urinary bladder tissues have been proposed. (See, e.g., U.S. Pat. Nos. 4,902,508, 4,956,178, 5,281,422, 5,554,389, 6,099,567 and 6,206,931.) In addition, Cook Biotech Inc. (West Lafayette, Ind.), currently manufactures a variety of medical products based upon small intestinal submucosa under the trademarks SURGISIS®, STRATASIS® and OASIS®.
Medical materials derived from liver basement membrane have also been proposed, for example in U.S. Pat. No. 6,379,710. As well, ECM materials derived from amnion (see, e.g., U.S. Pat. Nos. 4,361,552 and 6,576,618) and from renal capsule membrane (see, e.g., WO003002165) have been proposed for medical and/or cell culture applications.
Some investigators have reported that small intestinal submucosa (SIS) material has an improved biocompatibility that makes it a useful tissue scaffolding material. (Woods, et al., (2004), Biomaterials, 25 (3):515-525.) In Woods, it is hypothesized that the human umbilical vein endothelial cells cultured on SIS (HUVEC) deposited human basement membrane proteins to create what was termed a “conditioned” SIS (c-SIS). The surface properties of the c-SIS were hypothesized to be changed in such a way that, upon re-seeding of human umbilical vein endothelial cells on the c-SIS substrate, the cells exhibited enhanced organization of cellular junctures and an increase in metabolic activity, compared to HUVEC cells cultured on a native, non-conditioned SIS (n-SIS) substrate. The HUVEC cells cultured on c-SIS were reported to release lower amounts of pro-inflammatory prostaglandin PGI2 into the media, compared to HUVEC grown on n-SIS substrate. These effects were concluded to provide an SIS with improved properties as a tissue scaffolding material.
One group of researchers describe a conditioned cell culture media prepared from a culture of non-cancerous, non-tumor elasmobrach fish immune cells (i.e., cells obtained from epigonal organ or Leydig organ of elasmobrach fishes (e.g., sharks, skates, and rays)), and report the media to demonstrate anti-tumor activity (U.S. Pat. No. 7,309,501). The non-tumorous, non-cancerous fish immune cells are described as having released immune substances into the media of these cultures. These preparations do not describe the use of cells other than non-tumor, non-cancerous fish immune cells. Further, these preparations did not involve or reference the growth of cells on an extracellular matrix.
Carcinoma cells have been described as depositing fibrinogen. Fibrinogen is not converted to fibrin in the tumor stroma. The microenvironment of a tumor is composed of an amalgam of secreted soluble factors, solid material and tumor cells. Secreted soluble factors include chemokines such as CXCR-4 and CXCL-2, matrix altering enzymes such as matrix metalloproteinases (MMPs), protease inhibitors, and growth factors (e.g., vascular endothelial growth factor (VEGF)), all of which are stored in the surrounding ECM and released when required by the tumor cells (via protease-mediated degradation of the ECM). The surrounding ECM itself, which is composed of the interstitial matrix and basement membrane, constitutes the noncellular solid material, which is critical in the anchorage and migration of malignant cancer cells. (Alphonso, et al. (2009), Neoplasia, 11:1264-1271).
Cancer cells have been described as producing proteases (e.g., matrix metalloproteases, elastase, cathepsin-L) that remodel the ECM associated with a tumor. (Sund, et al., (2009), Cancer Metastasis Rev., 28:177-183). This remodeling leads to the release of substances sequestered in the ECM, as well as bioactive cleavage fragments from ECM proteins, such as collagen and proteoglycans. Sequestered substances which may be released into the tumor ECM include VEGF, which further influences tumor progression. Cancer cells also interact with the microenvironment through the release of soluble factors and through cell-matrix interactions. Examples of secretions or by-products include cadhereins, integrins, cytokines (IL-1, IL-6, IL-8, TNF-α, PDGF, EGF and TGF-β). Additional secreted molecules include endothelins, plasmin and uPA. (Zigrino, et al. (2005), Biochimie, 87:321-328).
Human breast cancer cells are shown to synthesize, secrete and deposit fibrinogen into the ECM. (Rybarczyk, et al. (2000), Cancer Res., 60: 2033-2039). Prostate cancer cells, in particular, have been reported to secrete bFGF, PDGF and TNF-α. (Kaminski, et al. (2006), Expert Opin. Ther. Targets, 14, 77-94). These and other products synthesized by various types of cancer cells have been described to contribute to the growth/spreading of cancer cells. However, it remains unknown whether tumor/cancer cell secretions and/or by-products demonstrate any anti-tumor and/or anti-cancer activities.
A need continues to exist in the medical arts for improved anti-cancer/anti-tumor preparations. In particular, improved preparations that are essentially cell free (acellular) that posses a tumor and/or cancer inhibiting activity continue to be pursued in the quest for improved anti-cancer and anti-tumor pharmaceuticals and vaccines. Improved tools for treatment and containment of cancer and tumor growth remain to be developed, and present the promise of a new generation of vaccines.